Letter pubs.acs.org/OrgLett
Highly Stereoselective Synthesis of Cyclopropylphosphonates Catalyzed by Chiral Ru(II)-Pheox Complex Soda Chanthamath, Seiya Ozaki, Kazutaka Shibatomi, and Seiji Iwasa* Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan S Supporting Information *
ABSTRACT: Ru(II)-Pheox-catalyzed asymmetric cyclopropanation of diethyl diazomethylphosphonate with alkenes, including α,β-unsaturated carbonyl compounds, afforded the corresponding optically active cyclopropylphosphonates in high yields and with excellent diastereoselectivity (up to 99:1) and enantioselectivity (up to 99% ee).
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to be an important factor in providing high diastereocontrol, and the cyclopropanation of diazomethylphosphonate with electron-deficient alkenes such as α,β-unsaturated carbonyl compounds has not been reported yet. Herein, we report a highly stereoselective synthesis of cyclopropylphosphonates by the catalytic asymmetric cyclopropanation of simple diethyl diazomethylphosphonate with various alkenes, including α,βunsaturated carbonyl compounds, catalyzed by a Ru(II)-Pheox complex. Recently, we reported that the complex, Ru(II)-Pheox, is extremely efficient in carbene transfer reactions, particularly cyclopropanation and N−H insertion reactions.10 Therefore, we attempted the cyclopropanation of styrene 5a with diethyl diazomethylphosphonate 6 in the presence of the Ru(II)-Pheox catalyst and first optimized the reaction conditions (Table 1). The cyclopropanation reaction of the simple diethyl diazomethylphosphonate 6 proceeded smoothly at room temperature in various solvents to afford the corresponding cyclopropylphosphonate 7 in an excellent trans/cis ratio (99:1 in most cases) and with high enantioselectivity (94−98% ee) (Table 1, entries 1−6). The cyclopropanation in toluene and CH3OH afforded low yields of the desired product due to the formation of the dimer from the diazo compound and an O−H insertion compound as the byproducts, respectively (Table 1, entries 2 and 5). Conducting the reaction at a lower temperature afforded lower yields and diastereoselectivity (Table 1, entries 6−8). The catalyst loading could be decreased to 1 mol %; however, the yield of 7 slightly decreased (Table 1, entry 9). With the optimal reaction conditions in hand, we further studied the generality of the asymmetric cyclopropanation of
ptically active cyclopropylphosphonate derivatives are important units and found in useful biologically active natural products or pharmacologically interesting compounds such as an analogue of nucleotide 1,1 an intermediate for HCV NS3 protease inhibitor 2,2 an analogue of L-Glu 3,3 and an analogue of fosmidomycin 44 (Figure 1). Moreover, cyclopropylphosphonates are also convenient intermediates for the synthesis of alkylidenecyclopropane derivatives by the Wadsworth−Emmons reaction.5
Figure 1. Examples of biologically relevant cyclopropylphosphonate derivatives.
Among the few methods developed for the synthesis of optically active cyclopropylphosphonate derivatives,1−4,6 the catalytic asymmetric cyclopropanation of alkenes with diazomethylphosphonates is the most efficient method from a stereoselective synthesis perspective. Over the past decade, efficient catalytic systems have been developed using chiral Cu(I), 7 Rh(II), 8 and Ru(II) 9 catalysts to afford the corresponding cyclopropylphosphonates in good yields and with high diastereo- and enantioselectivity. However, the bulkiness of the diazomethylphosphonate moiety was found © XXXX American Chemical Society
Received: April 19, 2014
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Table 1. Optimization of Reaction Conditionsa
entry
solvent
temp [°C]
yieldb [%]
trans/cisc
eed [%] trans
1 2 3 4 5 6 7 8 9e
THF toluene acetone dioxane CH3OH CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
rt rt rt rt rt rt 0 −10 rt
81 43 79 81 36 93 93 78 67
96:4 99:1 99:1 99:1 99:1 99:1 98:2 98:2 99:1
97 94 98 97 97 97 97 97 97
could also be easily cyclopropanated to afford the desired cyclopropane products in high yields and with high diastereoand enantioselectivity (Table 2, entries 2−4). Moreover, the cyclopropanation of styrene derivatives bearing an electronwithdrawing group such as chloro and nitro was also investigated (Table 2, entries 5 and 6). Interestingly, the enantioselectivity could be increased to 99% ee, while the diastereoselectivity decreased slightly to 98:2 dr. The cyclopropanation of α-methylstyrene smoothly afforded the corresponding cyclopropylphosphonate in a high yield and with high enantioselectivity (Table 2, entry 7). However, the diastereoselectivity was lower compared to that of the styrene without a substituent at the α-position. Vinylamine derivatives could also be cyclopropanated under the same reaction conditions to afford the corresponding 2-amino cyclopropylphosphonates in high yields and with high diastereo- and enantioselectivity (Table 2, entries 8 and 9).10b,e We also examined the cyclopropanation of inner alkenes such as trans-2hexene and cis-2-hexene; however, no cyclopropane products were observed due to the formation of a dimer from the diazo compound. Encouraged by the results obtained with the styrene and vinylamine derivatives, we next turned our attention to the cyclopropanation of diethyl diazomethylphosphonate with electron-deficient alkenes such as α,β-unsaturated esters, ketones, and amides (Table 3). Surprisingly, the reaction with
a
Reaction conditions: styrene (1 mmol) and diethyl diazomethylphosphonate (0.2 mmol) in the presence of Ru(II)-Pheox (3 mol %) under Ar. bIsolated yield. cDetermined by NMR. dDetermined by chiral HPLC analysis. eWith 1 mol % of catalyst.
various styrene derivatives in the presence of the chiral Ru(II)Pheox catalyst. As summarized in Table 2, styrene derivatives bearing an electron-donating group such as methyl or methoxy Table 2. Ru(II)-Pheox Catalyzed Asymmetric Cyclopropanation of Various Alkenes with Diethyl Diazomethylphosphonatea
Table 3. Ru(II)-Pheox Catalyzed Asymmetric Cyclopropanation of Various α,β-Unsaturated Carbonyl Compounds with Diethyl Diazomethylphosphonatea
a
Reaction conditions: alkenes 5 (1 mmol) and diethyl diazomethylphosphonate 6 (0.2 mmol) in the presence of catalyst (3 mol %) under Ar. bIsolated yield. cDetermined by NMR. dDetermined by chiral HPLC analysis. Bn = benzyl.
phenyl acrylate afforded cyclopropane product 7j in 65% yield and with an excellent trans/cis ratio (99/1) and enantioselectivity (98% ee). Moreover, 1-phenylprop-2-en-1-one and Nphenylacrylamide could also be cyclopropanated to afford the corresponding products, 7k and 7l, in high yields and with high diastereo- and enantioselectivity (Table 3, entries 2 and 3). Although the reaction was sensitive to the N-substituents of acrylamides in terms of the yield (Table 3, entries 4 and 5), to
a
Reaction conditions: alkenes 5 (1 mmol) and diethyl diazomethylphosphonate 6 (0.2 mmol) in the presence of catalyst (3 mol %) under Ar. bIsolated yield. cDetermined by NMR. dDetermined by chiral HPLC analysis. B
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the best of our knowledge, this is the first example of the catalytic asymmetric cyclopropanation of diazomethylphosphonate with electron-deficient alkenes. To determine the absolute configuration of cyclopropylphosphonates obtained using this catalytic system, we decided to synthesize a known compound, diethyl-2-(butyl)cyclopropylphosphonate 7o, by carrying out the Ru(II)-Pheoxcatalyzed cyclopropanation of diethyl diazomethylphosphonate with hex-1-ene 5o (Scheme 1). The (1R,2R) configuration was
and the diastereo- and enantioselectivity efficiency reported until now.1,3,14 In conclusion, we developed the highly stereoselective cyclopropanation of alkenes with diethyl diazomethylphosphonate by using the Ru(II)-Pheox complex as the catalyst. Moreover, the cyclopropanation of electron-deficient alkenes such as α,β-unsaturated ester, ketone, and amides could be carried out smoothly under mild reaction conditions to afford the corresponding cyclopropylphosphonate products in high yields and with excellent diastereo- and enantioselectivity. Furthermore, this method confirms the synthetic value of (−)-diethyl-2-(hydroxymethyl) cyclopropylphosphonate 8, a key intermediate in the synthesis of the analogue of nucleotide 1 and L-Glu 3. This efficient procedure can contribute to the progress of synthetic organic chemistry.
Scheme 1. Determination of Absolute Configuration of Diethyl-2-(butyl)cyclopropylphosphonate 7o
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures and characterization data of all the new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
confirmed by a comparison of the optical rotation value reported in the literature.11 Interestingly, although a normal alkene 5o was used as the substrate, highly stereoselective cyclopropanation could also be achieved (trans/cis = 99:1). Finally, to demonstrate the utility of our highly stereoselective cyclopropylphosphonate synthesis, we prepared a key intermediate in the reported synthesis of the analogue of nucleotide 1 and L-Glu 3 (Scheme 2). The optically active
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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Scheme 2. Preparation of (−)-Diethyl-2(hydroxymethyl)cyclopropylphosphonate 8, a Key Intermediate in the Synthesis of Analogue of Nucleotide 1 and L-Glu 3
ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for Scientific Research (C) (No. 23550179) from the Japan Society for the Promotion of Science.
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REFERENCES
(1) Midura, W. H.; Krysiak, J. A.; Mikołajczyk, M. Tetrahedron: Asymmetry 2003, 14, 1245−1249. (2) Pyun, H.-J.; Clarke, M. O.; Cho, A.; Casarez, A.; Ji, M.; Fardis, M.; Pastor, R.; Sheng, X. C.; Kim, C. U. Tetrahedron Lett. 2012, 53, 2360−2363. (3) Midura, W. H.; Krysiak, J.; Rzewnicka, A.; Supeł, A.; Łyżwa, P.; Ewas, A. M. Tetrahedron 2013, 69, 730−737. (4) Devreux, V.; Wiesner, J.; Goeman, J. L.; Eycken, J. V.; Jomaa, H.; Calenbergh, S. V. J. Med. Chem. 2006, 49, 2656−2660. (5) Lewis, R. T.; Motherwell, W. B. Tetrahedron Lett. 1988, 29, 5033−5036. (6) The method for the synthesis of racemic cyclopropylphosphonates: (a) Hirao, T.; Hagihara, M.; Ohshiro, Y.; Agawa, T. Synthesis 1984, 1, 60−61. (b) Dappen, M. S.; Pellicciari, R.; Natalini, B.; Monahan, J. B.; Chiorri, C.; Cordi, A. A. J. Med. Chem. 1991, 34, 161− 168. (c) Lewis, R. T.; Motherwell, W. B.; Shipman, M.; Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1995, 51, 3289−3302. (d) Yan, Z.; Zhou, S.; Kern, E. R.; Zemlicka, J. Tetrahedron 2006, 62, 2608−2615. (e) Davi, M.; Lebel, H. Chem. Commun. 2008, 4974−4976. (f) Krawczyk, H.; Wasek, K.; Kedzia, J.; Wojciechowski, J.; Wolf, W. M. Org. Biomol. Chem. 2008, 6, 308−318. (g) Amori, L.; Serpi, M.; Marinozzi, M.; Costantino, G.; Diaz, M. G.; Mermit, M. B.; Thomsen, C.; Pellicciari, R. Dokl. Akad. Nauk 2013, 450, 547−552. The method for the synthesis of optically active cyclopropylphosphonates: (h) Maux, P. L.; Abrunhosa, I.; Berchel, M.; Simonneaux, G.; Gulea, M.; Masson, S. Tetrahedron: Asymmetry 2004, 15, 2569−2573. (i) Amori, L.; Serpi, M.; Marinozzi, M.; Costantino, G.; Diaz, M. G.; Mermit, M. B.; Thomsen, C.; Pellicciari, R. Bioorg. Med. Chem. Lett. 2006, 16, 196−199. (j) Midura, W. H.; Sobczak, A.; Paluch, P. Tetrahedron Lett. 2013, 54, 223−226.
cyclopropylphosphonate 7p was readily synthesized by the cyclopropanation of diethyl diazomethylphosphonate with ethyl acrylate 5p in 78% yield and with high diastereoselectivity (99:1 dr). The reaction of 7p with 2 equiv of LiBH4 and 6 equiv of MeOH in THF afforded the desired product, (−)-diethyl-2-(hydroxymethyl)cyclopropylphosphonate 8, in 86% yield and with excellent diastereoselectivity (99:1 dr) and enantioselectivity (98% ee).12 This novel synthetic route represents a significant improvement in terms of fewer steps C
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(7) Charette, A. B.; Bouchard, J.-E. Can. J. Chem. 2005, 83, 533−542. (8) Lindsay, V. N. G.; Fiset, D.; Gritsch, P. J.; Azzi, S.; Charette, A. B. J. Am. Chem. Soc. 2013, 135, 1463−1470. (9) (a) Ferrand, Y.; Maux, P. L.; Simonneaux, G. Org. Lett. 2004, 6, 3211−3213. (b) Paul-Roth, C.; Montigny, F. D.; Rethoré, G.; Simonneaux, G.; Gulea, M.; Masson, S. J. Mol. Catal. A: Chem. 2003, 201, 79−91. (10) (a) Abu-Elfotoh, A.-M.; Phomkeona, K.; Shibatomi, K.; Iwasa, S. Angew. Chem., Int. Ed. 2010, 49, 8439−8443. (b) Chanthamath, S.; Phomkeona, K.; Shibatomi, K.; Iwasa, S. Chem. Commun. 2012, 48, 7750−7752. (c) Chanthamath, S.; Thongjareun, S.; Shibatomi, K.; Iwasa, S. Tetrahedron Lett. 2012, 53, 4862−4865. (d) Abu-Elfotoh, A.M.; Nguyen, D. P. T.; Chanthamath, S.; Phomkeona, K.; Shibatomi, K.; Iwasa, S. Adv. Synth. Catal. 2012, 354, 3435−3439. (e) Chanthamath, S.; Nguyen, D. T.; Shibatomi, K.; Iwasa, S. Org. Lett. 2013, 15, 772−775. (f) Chanthamath, S.; Takaki, S.; Shibatomi, K.; Iwasa, S. Angew. Chem., Int. Ed. 2013, 52, 5818−5821. (11) Absolute configuration of 7o was determined to be (1R,2R) by comparing the reported specific optical rotation: [α]D 25 −55.7 (c 1.00, CHCl3), Lit. [α]D 20 −50.1 (c 1.20, CHCl3) for 1R,2R-isomer, see: Krawczyk, H.; Wasek, K.; Kedzia, J. Synthesis 2009, 9, 1473−1476. (12) The reduction of the optically active cyclopropylphosphonate 7p was performed using the procedure by Midura; see: Reference 3. (13) The enantioselectivity was determined by benzoylation using benzoyl chloride (see Supporting Information). (14) Hah, J. H.; Gil, J. M.; Oh, D. Y. Tetrahedron Lett. 1999, 40, 8235−8238.
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